Compositions and Methods of Making Sustained Release Liquid Formulations

ABSTRACT

The present invention includes compositions and methods for the controlled release of active agents in a shelf-stable liquid formulation by blending one or more controlled release microbeads comprising one or more active agents, preparing a dense, thixotropic solution having a density that is at, or about, the density of the one or more microbeads comprising a thixotropic agent, water and one or more preservatives under conditions that reduce bubble formation and mixing the microbeads and the thixotropic solutions in a mixer that lacks scraping paddles.

FIELD OF INVENTION

The invention relates to compositions and methods of making liquid,sustained—release formulations, and more particularly, to the use ofmethods that eliminate the problems associated with the manufacture ofthe same.

BACKGROUND OF THE INVENTION

Without limiting the scope of the invention, its background is describedin connection with pharmaceutical agents that are delivered in anextended or sustained-release form, as an example.

One such method of making sustained release particles is taught in U.S.Pat. No. 6,120,787, issued to Gustafsson, et al, which teach a method ofpreparing parenterally administrable sustained release microparticles,that include preparing core particles in an aqueous medium that isessentially free from organic solvent, a biologically active substancebeing entrapped therein during or after said preparation, drying thecore particles and coating the same with a release-controlling polymerby air suspension technique so as to create a shell on the coreparticles without any detrimental exposure of the active substance toorganic solvent.

Another sustained-release composition includes an amorphous polymer aretaught in U.S. Pat. No. 6,613,358, issued to Randolph, et al., whichprovided for a sustained release composition for sustained release of apharmaceutical substance that includes a biocompatible polymer that ishighly amorphous and a pharmaceutical substance in a hydrophobic ioncomplex with an amphiphilic material. A compressed antisolvent methodfor manufacturing the composition it taught as are various product formsincorporating the composition and various uses for the composition.

Yet another sustained release drug formulation is taught in U.S. Pat.No. 5,980,945, issued to Ruiz in which a sustained release drugformulation includes a drug; a biodegradable polymer that is insolublein water; and an oil vehicle in which both the drug and the polymer aredissolved. The oil vehicle contains 10-100% by volume of apharmaceutically acceptable oil and 0-90% by volume a pharmaceuticallyacceptable liquid carrier for the drug or the polymer.

Finally, U.S. Pat. No. 5,674,533 issued to Santus, et al., teachespharmaceutical compositions for the controlled release of theanti-tussive, moguisteine, in a liquid suspension designed either asready-to-use and time-stable liquid formulations with a shelf-life of atleast two years, or as dry formulations that are reconstituted withwater when needed and then remain stable throughout the treatmentperiod. Santus teaches the use of coated microgranules for thecontrolled release of moguisteine having sizes ranging from 50 to 500μm, preferably from 90 to 300 μm, which are capable of remaining easilyin suspension in a liquid for extended times. The microgranules havemoguisteine core, with one or more optional plasticizers and excipients,granulated into microgranules having sizes smaller than 500 μm, uniformsurfaces, substantially spherical shapes, apparent densities of about500 to 600 g/l and very low friabilities, made by wet-kneadingmicronised moguisteine using water or a mixture of water and othersolvents. These initial microgranules are given controlled-releaseproperties by, a first coating having essentially hydrophiliccharacteristics, which isolates the microgranules; a second coatinghaving lipophilic characteristics on top of the first coating; and athird coating having hydrophilic characteristics.

SUMMARY OF THE INVENTION

The present invention addressed the problems associated with thedelivery of one or more active agents in a liquid dosage form undercontrolled conditions. Liquid formulations are preferred by many usersdue to the easy of delivery, namely, swallowing thereby leading toincreased compliance with dosing regimens. It has been found that manychildren and adults fail to comply with dosing instructions due to thesize, shape, taste and/or mouth-feel of, e.g., tablets, caplets and evengelcaps.

The present inventors have recognized that delivery of agents in liquidformulation is not only preferred by many users, but also that many ofthe materials and processing methods and equipment using in the industrytoday fail to deliver products and formulations that, e.g., areshelf-stable, do not separate on the shelf (both floating and settling),do not require vigorous shaking (which greatly affects dosingconsistency), the mouth-feel of the liquid (e.g., grainy, bitter,slimy), provide actual controlled, sustained, mixed or modified release.Finally, it was recognized that despite many decades of research anddevelopment, controlled-release formulations have not been amenable tolarge-scale production in facilities and to amounts that are permissiblefor industrial applicability of controlled-release liquid formulations.

Furthermore, it was found that many known techniques for eliminating theproblems commonly associated with the manufacture of controlled-releaseliquid formulations, and hence their widespread failure, did not solvethe problems. Examples of techniques that failed in certain forms of thedevelopment of the present invention included: inert gas sparging,vacuum, reducing mixer speeds and eliminating mixer (e.g., propeller)caviation in the mixing vessel. Despite using these techniquesindividually and in combination, none of these techniques solved theproblems of, e.g., separation and stability. A novel approach was neededto reach the present invention.

Following a detailed analysis of the many failures, it was found thatseveral problems associated with the actual manufacturing steps and thecompositions used were needed to address the problems solved herein. Forexample, it was observed that one problem associated with the use ofcontrolled release beads, many examples of which are well-known in theart, was the dissociation of the bead coating during mixing, in whichmixer paddles designed to scrape the sides of the vessels to increasemixing efficiency were also causing the beads to shear and break,thereby eliminating the sustained-release nature of the beads. Anotherexample was the floating of beads as the liquid formulation was testedfor shelf-stability, as air bubbles introduced during the manufacturingprocess were found to cling to, or form on, the beads thereby changingtheir nominal density from that calculated based on its manufacture.

More particularly, the present invention includes compositions andmethods for preparing a liquid, controlled-release formulation byblending one or more controlled release microbeads having one or moreactive agents, preparing a dense, thixotropic solution having a densitythat is at or about the density of the one or more microbeads, wherein athixotropic agent, water and one or more preservatives are mixed underconditions that reduce bubble formation, e.g., using a mixer that lacksscraping paddles. The one or more microbeads may include an entericcoat, a resin coat, a lacquer coat, a pH-sensitive coating, abiodegradable polymer matrix, a water soluble matrix, an ionic matrix,combinations and mixtures thereof. The one or more microbeads may alsoincludes one or more polymers selected from cellulose, ethylcellulose,methylcellulose, propylcellulose, methoxypropylcellulose, cellulosenitrate, poly(vinyl alcohol), poly(vinyl chloride), polystyrene,polyethylene, polypropylene, poly(ethylene-co-vinyl acetate),poly(hydroxybutyric acid), poly(hydroxyvalerianic acid-co-hydroxybutyricacid), poly(lactic acid), poly(glycolic acid), poly(lacticacid-co-glycolic acid), poly(ε(-caprolactones),poly(ε-caprolactone-co-DL-lactic acid), poly(maleic anhydride),polyamides, gelatin, chitosan, collagen,poly(hydroxyalkyl)-L-glutamines, poly(γ-ethyl-L-glutaminate-co-glutamicacid), poly(L-leucine-co-L-aspartic acid), poly(proline-co-glutamicacid), poly(alkyl 2-cyanoacrylates), polyurethanes, poly(methylmethacrylate), poly(methyl methacrylate-co-methacrylic acid) andpoly(methacrylate-co-hydroxypropyl methacrylate), polystyrene,polistirex, polacrilex and salts, combinations and mixtures thereof.

The method of the present invention increases the shelf-life andstability of the actives agents, e.g., by preventing the separation ofthe components by taking steps to reduce or eliminate bubble formationduring the manufacture of the controlled-release liquid formulation ofthe present invention. Steps of the present invention for minimizing,reducing and/or eliminating bubble formation include, but are notlimited to using the following steps alone or in combination: using adiaphragm pump to combine, e.g., the water and the thixotropic agent andone or more preservatives, colorants and flavorants; placing therecirculating tube below the surface of the liquid; adding liquids alongthe side of a vessel holding the liquid; sprinkling beads (e.g., one ormore beads that includes one or more active agents) onto the surface ofthe liquid; mixing the solution in the absence of one or more paddlesthat scrape the vessel; mixing the solution with a propeller mixer;mixing the solution with a propeller mixer at a speed that reduces orminimizes cavitation and combinations of two or more of these steps.

The controlled-release liquid formulation may include a portion of theone or more beads with an immediate release profile and another portionwith a controlled or delayed release profile. When using an ion-exchangematrix, bead or resin to retain the one or more active agents the liquidsolution will in some cases be a low-ionic strength, depending on thenature of the ion-exchange matrix and the one or more active agents. Theskilled artisan can easily determine the best matrix for a particularactive, determine the amount of loading (theoretical and empirical), andthe conditions for retention and release.

Examples of active agents that may be provided as part of the liquidformulations of the present invention include vitamins, minerals,nutritional supplements, herbal extracts, gums, gels, oils, salts,mixtures and combinations thereof. Pharmaceutical active agents mayinclude, e.g., protein, peptide, carbohydrate, polysaccharide,glycoprotein, lipid, hormone, growth factor, cytokine, interferon,receptor, antigen, allergen, antibody, antiviral, antifungal,antihelminthic, substrate, metabolite, cofactor, inhibitor, drug,nutrient, toxin, poison, explosive, pesticide, chemical warfare agent,biowarfare agent, biohazardous agent, infectious agent, prion,radioisotope, vitamin, heterocyclic aromatic compound, carcinogen,mutagen, narcotic, amphetamine, barbiturate, hallucinogen. In some casesthe liquid may be, eg., a vaccine for against a virus, bacterium,helminth and/or fungi, fragments, receptors or toxins thereof, e.g.,Salmonella, Streptococcus, Brucella, Legionella, E. coli, Giardia,Cryptosporidium, Rickettsia, spore, mold, yeast, algae, amoebae,dinoflagellate, unicellular organism, pathogen, cell, combinations andmixtures thereof. The one or more active agents may be a pharmaceuticalagent, an enzyme, a cytokine, a growth promoting agent, an antibody, anantigen, a hormone, a vaccine, a cell, a live-attenuated pathogen, aheat-killed pathogen, a virus, a bacteria, a fungi, a peptide, acarbohydrate, a nucleic acid, a lipid, mixtures and combinationsthereof.

Specific examples of active agents include: steroids, respiratoryagents, sympathomimetics, local anesthetics, antimicrobial agents,antiviral agents, antifungal agents, antihelminthic agents,insecticides, antihypertensive agents, antihypertensive diuretics,cardiotonics, coronary vasodilators, vasoconstrictors, β-blockers,antiarrhythmic agents, calcium antagonists, anti-convulsants, agents fordizziness, tranquilizers, antipsychotics, muscle relaxants, drugs forParkinson's disease, respiratory agents, hormones, non-steroidalhormones, antihormones, vitamins, antitumor agents, miotics, herbmedicines, herb extracts, antimuscarinics, interferons, immunokines,cytokines, muscarinic cholinergic blocking agents, mydriatics, psychicenergizers, humoral agents, antispasmodics, antidepressant drugs,anti-diabetics, anorectic drugs, anti-allergenics, decongestants,expectorants, antipyretics, antimigrane, anti-malarials,anti-ulcerative, anti-estrogen, anti-hormone agents, anesthetic agent,or drugs having an action on the central nervous system. For example,for use in the treatment of cold/cough symptoms the active agents mayinclude one or more antihistamines, anti-tussives, expectorants and thelike, e.g., pseudoephedrine, chlorpheniramine, dextromethorphan,guaifenesin, and salts thereof or mixtures of salts thereof. The liquidformulation may also include an analgesic or even a narcotic.

Examples of carriers for the actives of the present invention includeany degradable, partially degradable or non-degradable and generallybiocompatible polymer, e.g., polystirex, polypropylene, polyethylene,polacrilex, poly-lactic acid (PLA), poly-glycolic acid (PGA) and/orpoly-lactic polyglycolic acid (PGLA) in the form or a matrix or even abead.

The present invention also includes those liquid formulations made bythe methods disclosed and claimed herein. For example, specific liquidformulation may include one or more active agents available forimmediate, modified and/or extended or controlled release for use intreating cold/cough/allergy symptoms. The one or more actives forcold/cough/allergy may include one or more of the following:anti-tussives, anti-histamines, expectorants and analgesics. Forexample, the actives may include: pseudoephedrine, chlorpheniramine,dextromethorphan, guaifenesin, and salts thereof or mixtures of saltsthereof.

In another embodiment, the present invention includes a method forpreparing a liquid, controlled-release formulation by blending one ormore controlled release beads having one or more active agents with adense, thixotropic solution having a density that is at or about thedensity of the one or more beads and a thixotropic agent, water and oneor more preservatives under conditions that reduce bubble formation. Aliquid formulation is made by the method. Yet another method forpreparing a liquid, controlled-release formulation includes blending amixture comprising one or more controlled-release beads comprising oneor more active agents, a thickening agent and a surfactant by mixingwith a low cavitation propeller and recirculating the mixture under thesurface of the mixture so as to minimize bubble formation. In oneembodiment, the formulation includes between about 15-45 mgphenylephrine disposed in, on or about a resin, between about 2-8 mgchlorphineramine disposed in, on or about a resin per dose. Theformulation may also include between about 15-45 mg dextromethorphandisposed in, on or about a resin.

Yet another embodiment of the present invention is a method of preparinga liquid, controlled-release formulation by blending a mixturecomprising one or more active agents on or about a carrier a thickeningagent under conditions that minimize the introduction of air. Theconditions that minimize, reduce and/or eliminate the introduction ofair and/or air bubbles include one or more of the following steps usedalone, in combination and/or in any order: using a diaphragm pump tocombine, e.g., the water and the thixotropic agent and one or morepreservatives, colorants and flavorants; placing the recirculating tubebelow the surface of the liquid; adding liquids along the side of avessel holding the liquid; sprinkling beads (e.g., one or more beadsthat includes one or more active agents) onto the surface of the liquid;mixing the solution in the absence of one or more paddles that scrapethe vessel; mixing the solution with a propeller mixer; mixing thesolution with a propeller mixer at a speed that reduces or minimizescavitation and combinations of two or more of these steps.

Yet another method for preparing a liquid, controlled-releaseformulation of the present invention includes blending a mixture of oneor more controlled-release beads with one or more active agents on acarrier in a solution having a low ionic concentration and a thixotropicagent, under conditions that minimize the introduction of air bubbles.

BRIEF DESCRIPTION OF THE DRAWINGS

For a more complete understanding of the features and advantages of thepresent invention, reference is now made to the detailed description ofthe invention along with the accompanying figures and in which:

FIG. 1 is a flow-chart of the basic steps of the present invention;

FIG. 2 is a detailed flow chart of present invention;

FIG. 3 is another detailed flow chart of present invention;

FIG. 4 is another detailed flow chart of present invention;

FIG. 5 is a flowchart with the final steps of the present invention;

FIG. 6-8 are graphs that demonstrate the release profile of two activeagents in a liquid formulation of the present invention; and

FIG. 9-11 are graphs that demonstrate the release profile of thirdactive agents in a liquid formulation of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

While the making and using of various embodiments of the presentinvention are discussed in detail below, it should be appreciated thatthe present invention provides many applicable inventive concepts thatcan be embodied in a wide variety of specific contexts. The specificembodiments discussed herein are merely illustrative of specific ways tomake and use the invention and do not delimit the scope of theinvention.

To facilitate the understanding of this invention, a number of terms aredefined below. Terms defined herein have meanings as commonly understoodby a person of ordinary skill in the areas relevant to the presentinvention. Terms such as “a”, “an” and “the” are not intended to referto only a singular entity, but include the general class of which aspecific example may be used for illustration. The terminology herein isused to describe specific embodiments of the invention, but their usagedoes not delimit the invention, except as outlined in the claims.

As used herein, the terms “extended release,” “sustained release,” and“delayed release” are used to define a release profile to effectdelivery of an active over an extended period of time, defined herein asbeing between about 60 minutes and about 2, 4, 6, 8 or even 12 hours.Extended release may also be defined functionally as the release of over80 to 90 percent (%) of the active ingredient after about 60 minutes andabout 2, 4, 6 or even 8 hours. Extended release as used herein may alsobe defined as making the active ingredient available to the patient orsubject regardless of uptake, as some actives may never be absorbed bythe animal. Various extended release dosage forms may be designedreadily by one of skill in art as disclosed herein to achieve deliveryto both the small and large intestines, to only the small intestine, orto only the large intestine, depending upon the choice of coatingmaterials and/or coating thickness.

“Extended release” and “delayed release” formulations may be preparedand delivered so that release is accomplished at some generallypredictable location in the lower intestinal tract more distal to thatwhich would have been accomplished if there had been no delayed releasealterations. A method for delay of release is, e.g., a coating. Anycoatings should be applied to a sufficient thickness such that theentire coating does not dissolve in the gastrointestinal fluids at pHbelow about 5, but does dissolve at pH about 5 and above. It is expectedthat any anionic polymer exhibiting a pH-dependent solubility profilecan be used as an enteric coating in the practice of the presentinvention to achieve delivery to the lower gastrointestinal tract.Polymers and compatible mixtures thereof may be used to provide thecoating for the delayed or the extended release of active ingredients,and some of their properties, include, but are not limited to: shellac,also called purified lac, a refined product obtained from the resinoussecretion of an insect. This coating dissolves in media of pH>7.

As used herein, the term “thixotropic” is used to describe one or moreagents, e.g., certain gels, which liquefy when subjected to vibratoryforces like simple shaking, and then solidify again when left standing.Thixotropic behavior is observed when long-chain molecules tend toorient themselves in the direction of flow; as the applied force isincreased, the resistance to flow is decreased. Yet when high shearstress is removed, the solution will quickly revert to its originalviscous state. Some celluloses exhibit thixotropic behavior wherein thesolution returns to its viscous state over a period of time. Examples ofthixotropic agents for use with, e.g., food, pharmaceuticals, are wellknown in the art, e.g., “A time-dependent expression for thixotropicareas. Application to Aerosil 200 hydrogels,” M. Dolz, F. Gonzalez, J.Delegido, M. J. Hernandez, J. Pellicer, J. Pharm. Sci., Vol. 89, No. 6,pages 790-797 (2000), relevant portions incorporated herein byreference. Numerous examples of thixotropic agents, such as cellulose(e.g., carboxymethylcellulose), gums (e.g., xanthan), collagen, gelatin,aerogels and others are well known in the art and may be used with thepresent invention, e.g., U.S. Pat. Nos. 6,709,675; 6,838,449; 6,818,018,relevant portions incorporated herein by reference.

The pharmaceutical composition and/or the solid carrier particles can becoated with one or more enteric coatings, seal coatings, film coatings,barrier coatings, compress coatings, fast disintegrating coatings, orenzyme degradable coatings. Multiple coatings may be applied for desiredperformance. Further, one or more of the actives may be provided forimmediate release, pulsatile release, controlled release, extendedrelease, delayed release, targeted release, synchronized release, ortargeted delayed release. In fact, the formulation may includecombinations of typical pharmaceutical actives (e.g., pseudephedrin) andvitamins (e.g., Vitamin C), minerals (Ca, Mg, Zn, K) or othersupplements (e.g., St. John's Wort, echinacae, amino acids). Forrelease/absorption control, solid carriers can be made of variouscomponent types and levels or thicknesses of coats, with or without anactive ingredient. Such diverse solid carriers can be blended in adosage form to achieve a desired performance. The liquid formulationsmay be delivered to, and adapted for, oral, nasal, buccal, ocular,urethral, transmucosal, vaginal, topical or rectal delivery, althoughoral delivery is used mostly.

When formulated with microparticles or nanoparticles, the one or moreactives the release profile can easily be adapted by adding, e.g., ahard or soft gelatin coating, a starch coating, a resin or polymercoating and/or a cellulosic coating. Although not limited tomicroparticles or nanoparticles (as in, e.g., microcapsules ornanocapsules), such dosage forms may be further coated with, forexample, a seal coating, an enteric coating, an extended releasecoating, or a targeted delayed release coating. The term “entericcoating” as used herein relates to a mixture of pharmaceuticallyacceptable excipients that is applied to, combined with, mixed with orotherwise added to the carrier or composition. The coating may beapplied to an active that is compressed, molded or extruded and may alsoinclude: gelatin, and/or pellets, beads, granules or particles of thecarrier or composition. The coating may be applied through an aqueousdispersion or after dissolving in appropriate solvent. The carrier mayor may not be fully or partially biodegradable.

Carriers for use with the present invention include permeable andsemipermeable matrices or polymers that control the releasecharacteristics of the formulation. Such polymers include, for example,cellulose acylates, acetates, and other semi-permeable polymers such asthose described in U.S. Pat. No. 4,285,987 (hereby incorporated byreference), as well as the selectively permeable polymers formed by thecoprecipitation of a polycation and a polyanioni as disclosed in U.S.Pat. Nos. 3,173,876; 3,276,586; 3,541,005; 3,541,006 and 3,546,142(relevant portions incorporated herein by reference).

Other carriers for use with the present invention include, e.g., starch,modified starch, and starch derivatives, gums, including but not limitedto xanthan gum, alginic acid, other alginates, benitoniite, veegum,agar, guar, locust bean gum, gum arabic, quince psyllium, flax seed,okra gum, arabinoglactin, pectin, tragacanth, scleroglucan, dextran,amylose, amylopectin, dextrin, etc., cross-linked polyvinylpyrrolidone,ion-exchange resins, such as potassium polymethacrylate, carrageenan(and derivatives), gum karaya, biosynthetic gum, etc. Other usefulpolymers include: polycarbonates (linear polyesters of carbonic acid);microporous materials (bisphenol, a microporous poly(vinylchloride),micro-porous polyamides, microporous modacrylic copolymers, microporousstyrene-acrylic and its copolymers); porous polysulfones, halogenatedpoly(vinylidene), polychloroethers, acetal polymers, polyesters preparedby esterification of a dicarboxylic acid or anhydride with an alkylenepolyol, poly(alkylenesulfides), phenolics, polyesters, asymmetric porouspolymers, cross-linked olefin polymers, hydrophilic microporoushomopolymers, copolymers or interpolymers having a reduced bulk density,and other similar materials, poly(urethane), cross-linked chain-extendedpoly(urethane), poly(imides), poly(benzimidazoles), collodion,regenerated proteins, semi-solid cross-linked poly(vinylpyrrolidone).

Additional additives and their levels, and selection of a primarycoating material or materials will depend on the following properties:resistance to dissolution and disintegration in the stomach;impermeability to gastric fluids and drug/carrier/enzyme while in thestomach; ability to dissolve or disintegrate rapidly at the targetintestine site; physical and chemical stability during storage;non-toxicity; easy application as a coating (substrate friendly); andeconomical practicality.

Dosage forms of the compositions of the present invention can also beformulated as enteric coated delayed release oral dosage forms, i.e., asan oral dosage form of a pharmaceutical composition as described hereinthat uses an enteric coating to effect release in the lowergastrointestinal tract. The enteric coated dosage form will generallyinclude microparticles, microgranules, micropellets or microbeads of theactive ingredient and/or other composition components, which arethemselves coated or uncoated. The enteric coated oral dosage form mayalso be a capsule (coated or uncoated) containing pellets, beads orgranules of the solid carrier or the composition, which are themselvescoated or uncoated.

Active Pharmaceutical Ingredients. The one or more active agents thatare formulated in a self-stable manner using the present invention mayinclude a wide variety of uses, not just the traditional pharmaceuticalagents. Actives for use with the present invention in immediate and/orcontrolled release formulations may include systemically activetherapeutic agents, locally active therapeutic agents, disinfectingagents, chemical impregnants, cleansing agents, deodorants, fragrances,dyes, animal repellents, insect repellents, fertilizing agents,pesticides, herbicides, fungicides, and plant growth stimulants, and thelike. Some non-limiting examples of active agents are listedhereinbelow. Those skilled in the art will appreciate that any of thesecompounds may be used in the form of their pharmaceutically acceptablesalt forms, e.g., carboxylic acids, with counter-ions, e.g., potassium,sodium, calcium; as ionic combinations with, e.g., resins, polymers,beads, matrices; with sugars or sugar derivatives, e.g., malate,tannate; amino acids, lipids, oils or combinations, mixtures and thelike. In some embodiments, the present inventors have found that certainactives may be provided with two different salts, each of which may havea different solubility and/or release profile under, e.g., physiologicconditions. In fact, liquid formulation of present invention includescombinations of one or more of the following: immediate release,pulsatile release, controlled release, extended release, delayedrelease, targeted release, or targeted delayed release.

Some examples of active ingredients suitable for use in thepharmaceutical formulations and methods of the present inventioninclude: hydrophilic, lipophilic, amphiphilic or hydrophobic, and thatcan be solubilized, dispersed, or partially solubilized and dispersed,on or about a carrier. The active agent-carrier combination may becoated further to encapsulate the agent-carrier combination.Alternatively, an active ingredient may also be provided separately fromthe solid pharmaceutical composition, such as for co-administration.Such active ingredients can be any compound or mixture of compoundshaving therapeutic or other value when administered to an animal,particularly to a mammal, such as drugs, nutrients, cosmaceuticals,nutraceuticals, diagnostic agents, nutritional agents, and the like. Theactive agents listed below may be found in their native state, however,they will generally be provided in the form of a salt. The active agentslisted below include their isomers, analogs and derivatives.

In one embodiment, the active ingredient agent is hydrophobic.Hydrophobic active ingredients are compounds with little or no watersolubility. Intrinsic water solubilities (i.e., water solubility of theunionized form) for hydrophobic active ingredients are less than about1% by weight, and typically less than about 0.1% or 0.01% by weight.Suitable hydrophobic active ingredients are not limited by therapeuticcategory, and can be, for example, analgesics, anti-inflammatory agents,antihelmimthics, anti-arrhythmic agents, anti-bacterial agents,anti-viral agents, anti-coagulants, anti-depressants, anti-diabetics,anti-epileptics, anti-fungal agents, anti-gout agents, anti-hypertensiveagents, anti-malariale, anti-migrainc agents, anti-muscarinic agents,anti-neoplastic agents, erectile dysfunction improvement agents,immunosuppressants, anti-protozoal agents, anti-thyroid agents,anxiolytic agents, sedatives, hypnotics, neuroleptics, .beta.-Blockers,cardiac inotropic agents, corticosteroids, diuretics, anti-parkinsonianagents, gastro-intestinal agents, histamine receptor antagonists,keratolytics, lipid regulating agents, anti-anginal agents, cox-2inhibitors, leukotriene inhibitors, macrolides, muscle relaxants,nutritional agents, opioid analgesics, protease inhibitors, sexhormones, stimulants, muscle relaxants, anti-osteoporosis agents,anti-obesity agents, cognition enhancers, anti-urinary incontinenceagents, nutritional oils, anti-benign prostate hypertrophy agents,essential fatty acids, non-essential fatty acids, and mixtures thereof.Salts, isomers and derivatives of the above-listed hydrophobic activeingredients may also be used, as well as combinations and mixturesthereof.

Other examples of suitable hydrophobic active ingredients include:acetretin, albendazole, albuterol, aminoglutethimide, amiodarone,amlodipine, amphetamine, amphotericin B, atorvastatin, atovaquone,azithromycin, baclofen, beclomethasone, benezepril, benzonatate,betamethasone, bicalutanide, budesonide, bupropion, busulfan,butenafine, calcifediol, calcipotriene, calcitriol, camptothecin,candesartan, capsaicin, carbamezepine, carotenes, celecoxib,cerivastatin, cetirizine, chlorpheniramine, cholecalciferol, cilostazol,cimetidine, cinnarizine, ciprofloxacin, cisapride, clarithromycin,clemastine, clomiphene, clomipramine, clopidogrel, codeine, coenzymeQ10, cyclobenzaprine, cyclosporin, danazol, dantrolene,dexchlorpheniramine, diclofenac, dicoumarol, digoxin,dehydroepiandrosterone, dihydroergotamine, dihydrotachysterol,dirithromycin, donezepil, efavirenz, eposartan, ergocalciferol,ergotamine, essential fatty acid sources, etodolac, etoposide,famotidine, fenofibrate, fentanyl, fexofenadine, finasteride,fluconazole, flurbiprofen, fluvastatin, fosphenyloin, frovatriptan,furazolidone, gabapentin, gemfibrozil, glibenclamide, glipizide,glyburide, glimepiride, griseofulvin, halofantrine, ibuprofen,irbesartan, irinotecan, isosorbide dinitrate, isotretinoin,itraconazole, ivermectin, ketoconazole, ketorolac, lamotrigine,lansoprazole, leflunomide, lisinopril, loperamide, loratadine,lovastatin, L-thryroxine, lutein, lycopene, medroxyprogesterone,mifepristone, mefloquine, megestrol acetate, methadone, methoxsalen,metronidazole, miconazole, midazolam, miglitol, minoxidil, mitoxantrone,montelukast, nabumetone, nalbuphine, naratriptan, nelfinavir,nifedipine, nilsolidipine, nilutanide, nitrofurantoin, nizatidine,omeprazole, oprevelkin, oestradiol, oxaprozin, paclitaxel, paracalcitol,paroxetine, pentazocine, pioglitazone, pizofetin, pravastatin,prednisolone, probucol, progesterone, pseudoephedrine, pyridostigmine,rabeprazole, raloxifene, rofecoxib, repaglinide, rifabutine,rifapentine, rimexolone, ritanovir, rizatriptan, rosiglitazone,saquinavir, sertraline, sibutramine, sildenafil citrate, simvastatin,sirolimus, spironolactone, sumatriptan, tacrine, tacrolimus, tamoxifen,tamsulosin, targretin, tazarotene, telmisartan, teniposide, terbinafine,terazosin, tetrahydrocannabinol, tiagabine, ticlopidine, tirofibran,tizanidine, topiramate, topotecan, toremifene, tramadol, tretinoin,troglitazone, trovafloxacin, ubidecarenone, valsartan, venlafaxine,verteporfin, vigabatrin, vitamin A, vitamin D, vitamin E, vitamin K,zafirlukast, zileuton, zolmitriptan, zolpidem, and zopiclone. Of course,salts, isomers and derivatives of the above-listed hydrophobic activeingredients may also be used, as well combinations and mixtures thereof.

In other embodiments, the active ingredient is hydrophilic, however,combination of hydrophilic, hydrophobic and non-polar agents may also beused. The water solubility for hydrophilic active ingredients isgenerally greater than about 0.1% by weight, and typically greater thanabout 1% by weight. Suitable hydrophilic active ingredients include:analgesics, anti-inflammatory agents, antihelminthics, anti-arrhythmicagents, anti-bacterial agents, anti-viral agents, anti-coagulants,anti-depressants, anti-diabetics, anti-epileptics, anti-fungal agents,anti-gout agents, anti-hypertensive agents, anti-malarials,anti-migraine agents, anti-muscarinic agents, anti-neoplastic agents,erectile dysfunction improvement agents, immunosuppressants,anti-protozoal agents, anti-thyroid agents, anxiolytic agents,sedatives, hypnotics, neuroleptics, .beta.-Blockers, cardiac inotropicagents, corticosteroids, diuretics, anti-parkinsonian agents,gastro-intestinal agents, histamine receptor antagonists, keratolytics,lipid regulating agents, anti-anginal agents, cox-2 inhibitors,leukotriene inhibitors, macrolides, muscle relaxants, nutritionalagents, opioid analgesics, protease inhibitors, sex hormones,stimulants, muscle relaxants, anti-osteoporosis agents, anti-obesityagents, cognition enhancers, anti-urinary incontinence agents,nutritional oils, anti-benign prostate hypertrophy agents, essentialfatty acids, non-essential fatty acids, and mixtures thereof.

Other hydrophilic active ingredients include: a cytokine, apeptidomimetic, a peptide, a protein, a toxoid, a serum, an antibody, avaccine, a nucleoside, a nucleotide, a portion of genetic material, anucleic acid, or a mixture thereof. Other examples of suitablehydrophilic active ingredients include: acarbose; acyclovir; acetylcysteine; acetylcholine, chloride; alatrofloxacin; alendronate;aglucerase; amantadine hydrochloride; ambenomium; amifostine; amiloridehydrochloride; aminocaproic acid; amphotericin B; antihemophilic factor(human), antihemophilic factor (porcine); antihemophilic factor(recombinant), aprotinin; asparaginase; atenolol; atracurium besylate;atropine; azithromycin; aztreonam; BCG vaccine; bacitracin; becalermin;belladona; bepridil hydrochloride; bleomnycin sulfate; calcitonin human;calcitonin salmon; carboplatin; capecitabine; capreomycin sulfate;cefamandole nafate; cefazolin sodium; cefepime hydrochloride; cefixime;cefonicid sodium; cefoperazone; cefotetan disodium; cefotaxime;cefoxitin sodium; ceftizoxime; ceftriaxone; cefuroxime axetil;cephalexin; cephapirin sodium; cholera vaccine; chorionic gonadotropin;cidofovir; cisplatin; cladribine; clidinium bromide; clindamycin andclindamycin derivatives; ciprofloxacin; clodronate; colistimethatesodium; colistin sulfate; corticotropin; cosyntropin; cromolyn sodium;cytarabine; dalteparin sodium; danaparoid; desferrioxamine; denileukindiflitox; desmopressin; diatrizoate meglumine and diatrizoate sodium;dicyclomine; didanosine; dirithromycin; dopamine hydrochloride; dornasealpha; doxacurium chloride; doxorubicin; etidronate disodium;enalaprilat; enkephalin; enoxaparin; enoxaprin sodium; ephedrine;epinephrine; epoetin alpha; erythromycin; esmolol hydrochloride; factorIX; famciclovir; fludarabine; fluoxetine; foscarnet sodium; ganciclovir;granulocyte colony stimulating factor, granulocyte-macrophagestimulating factor; growth hormones—recombinant human; growthhormone-1-bovine; gentamycin; glucagon; glycopyrolate; gonadotropinreleasing hormone and synthetic analogs thereof; GnRH; gonadorelin;grepafloxacin; haemophilus B conjugate vaccine; Hepatitis A virusvaccine inactivated; Hepatitis B virus vaccine inactivated; heparinsodium; indinavir sulfate; influenza virus vaccine; interleukin-2;interleukin-3; insulin-human, insulin lispro; insulin procine; insulinNPH; insulin aspart; insulin glargine; insulin detemir; interferonalpha; interferon beta; ipratropium bromide; ifosfamide; Japaneseencephalitis virus vaccine; lamivudine; leucovorin calcium; leuprolideacetate, levofloxacin; lincomycin and lincomycin derivatives; lobucavir;lomefloxacin; loracarbef; mannitol; is measles virus vaccine;meningococcal vaccine; menotropins; mepenzolate bromide; mesalamine;methenamine; methotrexate; methscopolamine; metformin hydrochloride;metoprolol; mezocillin sodium; mivacurium chloride; mumps viral vaccine;nedocromil sodium; neostigmine bromide; neostigmine methyl sulfate;neurontin; norfloxacin; octreotide acetate; ofloxacin; olpadronate;oxytocin; pamidronate disodium; pancuronium bromide; paroxetine;perfloxacin; pentamidine isethionate; pentostatin; pentoxifylline;periciclovir; pentagastrin; pentholamine mesylate; phenylalanine;physostigmine salicylate; plague vaccine; piperacillin sodium; plateletderived growth factor-human; pneumococcal vaccine polyvalent; poliovirusvaccine inactivated; poliovirus vaccine live (OPV); polymyxin B sulfate;pralidoxime chloride; pramlintide, pregabalin; propafenone;propenthaline bromide; pyridostigmine bromide; rabies vaccine;residronate; ribavarin; rimantadine hydrochloride; rotavirus vaccine;salmeterol xinafoate; sinealide; small pox vaccine; solatol;somatostatin; sparfloxacin; spectinomycin; stavudine; streptokinase;streptozocin; suxamethonium chloride; tacrine hydrochloride; terbutalinesulfate; thiopeta; ticarcillin; tiludronate; timolol; tissue typeplasminogen activator; TNFR:Fc; TNK-tPA; trandolapril; trimetrexategluconate; trospectinomycin; trovafloxacin; tubocurarine chloride; tumornecrosis factor; typhoid vaccine live; urea; urokinase; vancomycin;valacyclovir; valsartan; varicella virus vaccine live; vasopressin andvasopressin derivatives; vecuronium bromide; vinblastine; vincristine;vinorelbine; vitamin B12; warfarin sodium; yellow fever vaccine;zalcitabine; zanamivir; zolendronate; zidovudine; pharmaceuticallyacceptable salts, isomers and derivatives thereof; and mixtures thereof.

A wide variety of therapeutically active agents can be used inconjunction with the present invention. The therapeutically activeagents (e.g. pharmaceutical agents) which may be used in thecompositions of the present invention include both water soluble andwater insoluble drugs. Examples of such therapeutically active agentsinclude antihistamines (e.g., dimenhydrinate, diphenhydramine,chlorpheniramine and dexchlorpheniramine maleate), analgesics (e.g.,aspirin, codeine, morphine, dihydromorphone, oxycodone, etc.),non-steroidal anti-inflammatory agents (e.g., naproxyn, diclofenac,indomethacin, ibuprofen, sulindac), anti-emetics (e.g., metoclopramide),anti-epileptics (e.g., phenyloin, meprobamate and nitrezepam),vasodilators (e.g., nifedipine, papaverine, diltiazem and nicardirine),anti-tussive agents and expectorants (e.g., codeine phosphate),anti-asthmatics (e.g. theophylline), antacids, anti-spasmodics (e.g.,atropine, scopolamine), antidiabetics (e.g., insulin), diuretics (e.g.,ethacrynic acid, bendrofluazide), anti-thypotensives (e.g., propranolol,clonidine), antihypertensives (e.g, clonidine, methyldopa),bronchodilators (e.g., albuterol), steroids (e.g., hydrocortisone,triamcinolone, prednisone), antibiotics (e.g., tetracycline),antihemorrhoidals, hypnotics, psycho-tropics, antidiarrheals,mucolytics, sedatives, decongestants, laxatives, vitamins, stimulants(including appetite suppressants such as phenylpropanolamine), as wellas salts, hydrates, and solvates of the same. The above list is notmeant to be exclusive.

In certain embodiments, the therapeutically active agent compriseshydromorphone, oxycodone, dihydrocodeine, codeine, dihydromorphine,morphine, buprenorphine, salts, hydrates and solvates of any of theforegoing, mixtures of any of the foregoing, and the like. In otherembodiments, the active agent is a locally active therapeutic agent andthe environment of use may be, e.g., the gastrointestinal tract, or bodycavities such as the oral cavity, periodontal pockets, surgical wounds,the rectum or vagina. The liquid formulations of the present inventionmay be provided orally, topically, subcutaneously, intramuscularly,intraperitoneally, intraocularly, intraossealy, nasally, urethrally,mucosally, vaginally, rectally, intradurally, epidurally and the like.The liquid formulation of the present invention may also be provided asa mist, e.g., to the deep lung (alveolarly).

Locally active pharmaceutical agents of use with the present inveentioninclude antifungal agents (e.g., amphotericin B, clotrimazole, nystatin,ketoconazole, miconazol, etc.), antibiotic agents (penicillins,cephalosporins, erythromycin, tetracycline, aminoglycosides, etc.),antiviral agents (e.g, acyclovir, idoxuridine, etc.), breath fresheners(e.g. chlorophyll), antitussive agents (e.g., dextromethorphanhydrochloride), anti-cariogenic compounds (e.g. metallic salts offluoride, sodium monofluorophosphate, stannous fluoride, aminefluorides), analgesic agents (e.g., methylsalicylate, salicylic acid,etc.), local anesthetics (e.g., benzocaine), oral anti-septics (e.g.,chlorhexidine and salts thereof, hexylresorcinol, dequalinium chloride,cetylpyridinium chloride), anti-flammatory agents (e.g., dexamethasone,betamethasone, prednisone, prednisolone, triamcinolone, hydrocortisone,etc.), hormonal agents (oestriol), antiplaque agents (e.g, chlorhexidineand salts thereof, octenidine, and mixtures of thymol, menthol,methysalicylate, eucalyptol), acidity reducing agents (e.g., bufferingagents such as potassium phosphate dibasic, calcium carbonate, sodiumbicarbonate, sodium and potassium hydroxide, etc.), and toothdesensitizers (e.g., potassium nitrate). This list is not meant to beexclusive. Other embodiments of the present invention includedisinfecting agents, e.g., chlorine compounds such as calciumhypochlorite, and the environment of use is a surrounding body of water,e.g. a recreational pool. The active may be one or more cleansingagents, a germicide, a deodorant, a surfactant, a fragrance, a perfume,a sanitizer, and/or a dye, and the environment of use is an aqueoussolution, e.g. a urinal or toilet bowl. Examples of fragrances include:perfume oils, volatile—compounds including esters, ethers aldehydes,alcohols, unsaturated hydrocarbons, terpenes, and other ingredients wellknown in the art.

The liquid formulation may also include active agents with one or morechemical agents, e.g., fertilizers, animal repellents, insectrepellents, pesticides, herbicides, fungicides, plant growth stimulants,and the environment of use is, e.g., anywhere around the home, e.g.soil, trees etc. The fertilizer may be, for example, a nitrogencontaining compound such as urea, urea formaldehyde composites,potassium nitrate, potassium sulfate, potassium chloride, ammoniumnitrate, ammonium sulfate, monoammonium phosphate, dibasic ammoniumphosphate, ammoniated super-phosphoric acid, micronutrient ingredientssuch as trace elements of iron, zinc, manganese, copper, boron,molybdenum, and mixtures of any of the foregoing. In these embodiments,the thickness of the controlled release coating will depend upon, amongother things, the desired rate and overall time period for release of aneffective amount of the active agent. In some circumstances where arelatively long time period of efficacy is desired, the substrate may becoated to a relatively high weight gain of, e.g., up to 50% or more.

The examples herein include pharmaceutically active compounds useful inthe practice of the present invention, e.g., antihistamines,decongestants, antitussives and/or expectorants. Other actives for usewith the present invention include, but are not limited to:non-steroidal anti-inflammatory drugs (NSAIDs) and other analgesic drugssuch as acetominophen and phenacetin. These materials are incorporatedinto the immediate or controlled release formulations of the inventionin amounts governed by the desired release characteristics of thematerial in such excipient base and such that conventional dosagescomply with applicable federal Food and Drug Administration (FDA) orother regulations.

Decongestants useful with the present invention (along with a salt form)are phenylephrine (bitartrate, tannate, HBr, HCl), phenylpropanolamine(HCl) and pseudoephedrine (HCl). Furthermore, a number of herbal and/ornatural decongestants are known in the art, all of which may be usedwith the present invention.

Expectorants for use with the present invention include, e.g.,guaifenesin, terpin hydrate, (glyceryl guaiacolate), potassium (iodide,citrate) and potassium guaicolsulfonate. Other expectorants, whetherindividual ingredients or combinations of ingredients may be used withthe present invention. Furthermore, a number of herbal and/or naturalexpectorants are known in the art, all of which may be used with thepresent invention, e.g., Oregano Leaf Extract 25-500 mg (which may be aliquid extract), Red Clover 25-500 mg, Buckthorn Root 25-500 mg, orFenugreek 25-500 mg, or mixtures thereof.

Examples of antihistamines for use with the present invention (e.g., insalt form) are chlorpheniramine (maleate), brompheniramine (maleate),dexchlorpheniramine (maleate), dexbrompheniramine (maleate),triprolidine (HCl), diphenhydramine (HCl), doxylamine (succinate),tripelennamine (HCl), cyproheptatine (HCl), bromodiphenhydramine (HCl),phenindamine (tartrate), pyrilamine (maleate, tannate) and azatadine(maleate). Antitussives that may be used with the present invention(with salt form) include: caramiphen (edisylate), dextromethorphan (HBr)and codeine (phosphate, sulfate). A number of herbal and/or naturalantihistamines are known in the art, all of which may be used with thepresent invention.

Other actives may also be included with the present invention, e.g.,non-steroidal anti-inflammatory drugs (NSAIDs) such as propionic acidderivatives; acetic acid derivatives; fenamic acid derivatives;biphenylcarboxylic acid derivatives; and oxicams. Examples of propionicacid derivatives include: ibuprofen, naproxen, ketoprofen, flurbiprofen,fenoprofen, suprofen, fenbufen, and fluprofen may be mentioned aspreferred compounds. Acetic acid derivatives derivatives include:tolmetin sodium, zomepirac, sulindac and indomethacin. Fenamic acidderivatives derivatives include: mefenamic acid and meclofenamatesodium. Diflunisal and flufenisal are biphenylcarboxylic acidderivatives, while oxicams include piroxicam, sudoxicam and isoxicam.Other analgesics for use with the present invention includeacetominophen and phenacetin. Naproxen may be present in amounts ofabout 50 to about 250 milligrams per liquid dose, however, naproxen maybe used in amounts of between about 100 and about 150 milligrams perliquid dose.

Phenylephrine may be present in amounts of between about 15 and about 60milligrams per liquid dose. Phenylephrine is generally in amounts ofabout 5 to about 30 milligrams per liquid dose, with half or less ofthat amount used in a pediatric form of the formulation. In one exampleof the present invention, phenylephrine is provided in the amount ofabout 15 mg for extended release. Phenylephrine hydrochloride is anorally effective nasal decongestant. Chemically it is(S)-3-hydroxy-α[(methylamino) methyl]benzenemethanol hydrochloride.Phenylepherine is a synthetic, optically active sympathomimetic aminethat has one hydroxyl group on the benzene ring. The hydroxyl group isplaced in the position meta to the aliphatic side chain. The metaposition affords optimal activity and phenylepherine (neo-synephrine)replaced an older preparation, synephrine, in which the hydroxyl was inthe para position.

Phenylephrine hydrochloride is available in the form of the levorotatoryisomer, a white, odorless, non-hygroscopic, crystalline compoundpossessing a bitter taste. Phenylephrine hydrochloride has a meltingpoint of 140-145 degrees C. and is freely soluble in water and alcohol.Decongestant compounds in the form of their free bases as well as theirsalts, e.g., hydrochloride, citrate, maleate, tannate, etc., are wellknown.

Dextromethorphan may be present in amounts of between about 5 and about20 milligrams per liquid dose, with a general range of about 10 to about15 milligrams. Brompheniramine may be present in amounts of betweenabout 0.5 and about 4.0 milligrams per liquid dose with a general rangeof about 2.0 milligrams per liquid dose. Half or less of that amount maybe used in a pediatric form of the formulation.

The present invention may also include chlorpheniramine, which is anantihistamine used to relieve, e.g., allergic rhinitis (seasonalallergy). The symptoms of allergic rhinitis include: sneezing, runnynose, itching, and watery eyes. Chlorpheniramine may also be used totreat immediate allergic reactions. Chlorpheniramine may be providedalone and in combination with other prescription or nonprescriptiondrugs, e.g., to treat symptoms of allergy, colds, and upper respiratoryinfections.

The present invention may also include one or more analgesics, e.g.,acetaminophen may be present in amounts of up to about 600 milligramsper liquid dose. Generally, acetaminophen is present in amounts of about50 to about 200 milligrams per liquid dose. Another example isibuprofen, which may be used in amounts of, e.g., 150 milligrams, with arange of about 50 and about 150 milligrams per dose being usedgenerally. Half or less of that amount may be used in a pediatric formof the formulation.

In one example of the present invention, an expectorant (e.g.,Guaifenesin DC) is provided at lower doses and is made availableimmediately for absorption, followed by a lower dose of a decongestant(e.g., phenylephrine) which is release slowly over, e.g., about 1 to 8hrs. This release profile makes the product more efficacious since thelarge amount of expectorant begins to break up mucus prior to the timethe decongestant is released to provide long acting decongestantactivity after mucus breakdown has begun.

Generally, guaifenesin is present in amounts of about 10 to about 600milligrams per liquid dose. Guaifenesin may be present in amounts of100, 150, 200, 300, 400, 440, 500 or even 600 or more milligrams perliquid dose. In one example, guaifenesin is present in amounts of about100 to about 200 milligrams per liquid dose, with half or less of thatamount used in a pediatric form of the formulation.

In one example, 400 milligrams of guaifenesin are included as an activefor immediate release. Guaifenesin is an expectorant that increases theoutput of phlegm (sputum) and bronchial secretions by reducingadhesiveness and surface tension. The increased flow of less viscoussecretions promotes cilliary action and facilitates the removal ofmucus. Hence, expectorants such as guaifenesin change a dry,unproductive cough to one that is more productive and less frequent.Guaifenesin, known chemically as 3(2-methoxyphenoxy)-1,2-propanediol, isa crystalline powder soluble in water and alcohol. It is indicated inthe USP Drug information as an expectorant for the symptomatic relief ofcough due to colds and minor upper respiratory infections.

Excipients for use with the present invention are well known to those ofskill in the art and include humectants such as glycerin and propyleneglycol, preservatives such as sodium benzoate and paraben, sweetenerssuch as sodium saccharin, corn syrup and sorbitol solutions, menthol andvarious flavoring and coloring agents. The pharmaceutically activecompounds and excipients for human use should be of N.F. or U.S.P.grade.

For certain actives it may be useful to provide buffering agents (orbufferants), where the acid is a pharmaceutically acceptable acid, suchas hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid,nitric acid, boric acid, phosphoric acid, acetic acid, acrylic acid,adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbicacid, benzoic acid, boric acid, butyric acid, carbonic acid, citricacid, fatty acids, formic acid, fumaric acid, gluconic acid,hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid,methanesulfonic acid, oxalic acid, para-bromophenylsulfonic acid,propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid,succinic acid, tannic acid, tartaric acid, thioglycolic acid,toluenesulfonic acid and uric acid, and where the base is apharmaceutically acceptable base, such as an amino acid, an amino acidester, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodiumhydrogen carbonate, aluminum hydroxide, calcium carbonate, magnesiumhydroxide, magnesium aluminum silicate, synthetic aluminum silicate,synthetic hydrotalcite, magnesium aluminum hydroxide,diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine,triethylamine, triisopropanolamine, or a salt of a pharmaceuticallyacceptable cation and acetic acid, acrylic acid, adipic acid, alginicacid, alkanesulfonic acid, an amino acid, ascorbic acid, benzoic acid,boric acid, butyric acid, carbonic acid, citric acid, a fatty acid,formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid,isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalicacid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonicacid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaricacid, thioglycolic acid, toluenesulfonic acid, and uric acid.

In some formulations additives may also include: chelating agents (suchas EDTA and EDTA salts); colorants or opaquants (such as titaniumdioxide, food dyes, lakes, natural vegetable colorants, iron oxides,silicates, sulfates, magnesium hydroxide and aluminum hydroxide);coolants (e.g., trichloroethane, trichloroethylene, dichloromethane,fluorotrichloromethane); cryoprotectants (such as trehelose, phosphates,citric acid, tartaric acid, gelatin, dextran and mannitol); and diluentsor fillers (such as lactose, mannitol, talc, magnesium stearate, sodiumchloride, potassium chloride, citric acid, spray-dried lactose,hydrolyzed starches, directly compressible starch, microcrystallinecellulose, cellulosics, sorbitol, sucrose, sucrose-based materials,calcium sulfate, dibasic calcium phosphate and dextrose).

Substrates. A powder constitutes a finely divided (milled, micronized,nanosized, precipitated) form of an active ingredient or additivemolecular aggregates or a compound aggregate of multiple components or aphysical mixture of aggregates of an active ingredient and/or additives.Such substrates may be formed of various materials known in the art,such as, for example: sugars, such as lactose, sucrose or dextrose;polysaccharides, such as maltodextrin or dextrates; starches;cellulosics, such as microcrystalline cellulose or microcrystallinecellulose/sodium carboxymethyl cellulose; inorganics, such as dicalciumphosphate, hydroxyapitite, tricalcium phosphate, talc, or titania; andpolyols, such as mannitol, xylitol, sorbitol or cyclodextrin.

It should be emphasized that a substrate need not be a solid material,although often it will be a solid. For example, the encapsulation coaton the substrate may act as a solid “shell” surrounding andencapsulating a liquid, semi-liquid, powder or other substrate material.Such substrates are also within the scope of the present invention, asit is ultimately the carrier, of which the substrate is a part, whichmust be a solid.

Excipients. The solid pharmaceutical compositions suspended in theliquid formulation of the present invention may include optionally oneor more additives, sometimes referred to as additives. The excipientsmay be contained in an encapsulation coat in compositions, which includean encapsulation coat, or can be part of the solid carrier, such ascoated to an encapsulation coat, or contained within the componentsforming the solid carrier. Alternatively, the excipients can becontained in the pharmaceutical composition but not part of the solidcarrier itself.

Solubilizers. The pharmaceutical compositions of the present inventionmay include optionally one or more solubilizers, i.e., additives toincrease the solubility of the pharmaceutical active ingredient or othercomposition components in the solid carrier. It has been recognized bythe present inventors that guaifenesin, in fact, acts as a solubilizerfor phenylephrine, and is used as such in the examples provided herein.Other solubilizers are known in the art. Mixtures of solubilizers arealso within the scope of the invention and are readily available fromstandard commercial sources.

The amount of solubilizer that may be included in compositions of thepresent invention is not particularly limited. Of course, when suchcompositions are administered to a patient, the amount of a givensolubilizer is limited to a bioacceptable amount, which is readilydetermined by one of skill in the art. In some circumstances, it may beadvantageous to include amounts of solubilizers far in excess ofbioacceptable amounts, for example, to maximize the concentration ofactive ingredient, with excess solubilizer removed prior to providingthe composition to a patient using conventional techniques, such asdistillation or evaporation.

The following are general instructions common to most liquidmanufacturing as will be known to the skilled artisan. For example,first, it is determined is all of the raw materials are available forthis manufacturing process. All of the raw materials are checked forcorrect identity and Quality Assurance release. All personnel involvedin the manufacturing process must be familiar with the activeingredients Material Safety Data Sheet and for those involved in themanufacturing process, these must wear appropriate attire and use theappropriate safety equipment. Standard microbiological precautions arefollowed, e.g., avoidance of contact with the raw materials and use ofgloves during the manufacturing process. When using water, water purityis verified and use of a Purified Water System is recommended. Prior touse allow the water to run to waste for 15 seconds. Assure that thewater quality is greater than 14 megohm-cm (MΩ-cm) on the seconddeionized water finishing tank.

FIG. 1 is a flow chart 100 that summarizes the basic steps in the methodof the present invention. In this flow chart 100, four basic branchesand processing steps or systems are used to reach a final mixing orblending step (102), each of which provides one component that may beused with the present invention. In block 104, a thickening agent isadded to a vessel or container that will provide, e.g., density controlto the final solution. The thickening agent, e.g., a syrup (corn, rice,wheat, soy, maple, pine) is heated to decrease its viscosity (block 106)for a sufficient time to provide an even temperature and/or decrease itsviscosity without burning the thickener. In block 108, water (roomtemperature or heated) is slowly added to the thickening agent along thesides of the vessel and at a rate that minimizes the introduction of airor bubbles to the thickening agent. The mixing step will generally usebelow the surface mixing, as with a propeller driven, variable speedmixer at speeds and rates that minimize, reduce or eliminate bladecavitation, thereby reducing the amount of gas or air that enters themixture. The blended water and thickener are then allowed to rest atblock 110 and are stored pending further steps.

In block 112, one or more preservatives are added to a vessel orcontainer and dissolved in accordance with the manufacturersinstructions, e.g., by adding a solvent (block 114) that may be water ora polar or non-polar solvent. Again, the mixing and blending will beconducted so as to minimize the introduction of air or bubbles into themixture. To further reduce the likelihood of bubble formation, in block116, a surfactant is added, again taking care to minimize bubbleformation. In some cases it may be appropriate to de-gas the solution atthis stage by, e.g., applying a vacuum or allowing the mixture tosettle. Finally, in block 118, the preservative/surfactant mixture isblended and stored for further processing. The mixing step willgenerally use below the surface mixing, as with a propeller driven,variable speed mixer at speeds and rates that minimize, reduce oreliminate blade cavitation, thereby reducing the amount of gas or airthat enters the mixture.

In another branch of the flow chart 100, a thixotropic agent is added(block 120) to a vessel and the water is added. The water added to thethixotropic agent may be room temperature or higher to allow thethixotropic agent to swell (block 122). Finally, once the thixotropicagent has swelled it is mixed to clarify to the maximum extent possibleat block 124. Again, the mixing step will generally use below thesurface mixing, as with a propeller driven, variable speed mixer atspeeds and rates that minimize, reduce or eliminate blade cavitation,thereby reducing the amount of gas or air that enters the mixture.

The one or more active agents are selected and prepared (block 126),obtained or purchased. The amount of active is calculated and theappropriate amounts are weighted (block 128). If the active is notpre-coated, in block 130, the beads, particles, polymers, resins, etc.may be coated as described hereinbelow or using any number of coatingmaterials and methods known to the skilled artisan. Generally, thedensity and/or coefficient of viscosity of the final coated particleswith the active agent will be at, around or about that of the combinedthickening and thixotropic agent (to minimize the need for mixing of theliquid formulation prior to use). One advantage of using a thixotropicagent is that it reduces the need to closely match the densities of theactive particles and the final solution, as the thixotropic agent “gels”when standing, thereby limiting the amount of settling of the activeduring a normal, short-term dosing period (e.g., 1-day to 2 weeks).Finally, the active agents (which may still be dry) may be mixed withone or more excipients, coating, flavorings, color and the like (whichmay also be dry) and the mixture is blended (block 132).

The four branches depicted in flow chart 100 may be combined into lessor divided into more branches depending on the actives, excipients,thickeners and thixotropic agents used. For example, is the actives aredry and the colorants, flavorants, etc., are not, then these may beadded to a liquid solution (e.g., at blocks 110, 118 and/or 124). It mayalso be advantageous to mix actives (beads, particles, polymers, etc.)in with liquid portions and/or in water.

Example 1

Capsule shells and process: 7.5% phenylephrine immediate release beadswhere used as starting material. A portion of this lot was transferredto a rotating pan. Phenylephrine was added to the beads using ofpharmaceutical glaze. The beads were then allowed to roll and cure for 6hours before sustained release coating was added. In-order to developthe product, four different levels of sustained release coating amountswere added. In one example, 10.93 Kgs of phenylephrine were added to thebeads using 4.32 Kgs of pharmaceutical glaze. The beads were thenallowed to roll and cure for 6 hours before sustained release coatingwas added. Alternatively, the encapsulation coat may be prepared by airsuspension chilling, air suspension drying, compression,cryopelletization, encapsulation, extrusion, lyophilization, molding,spheronization, spray chilling, spray congealing, and spray drying.

In order to develop the product four different levels of sustainedrelease coating amounts were added. The first was 7.15 kg's of SR mix #1and 4.96 kg's of pharmaceutical glaze. Once this loading was complete5.0 kg's were removed for drying and testing. The second load consistedof 4.75 kg's of SR mix #1 and 2.68 kg's of pharmaceutical glaze. Again5.0 kg's of beaded material was removed for drying at 40° C. andtesting. The third load consisted of 5.92 kg's SR mix #1 and 3.43 kg'sof glaze. After application another 5.0 kg's of beaded material wasremoved from the pan for drying at 40° C. and testing. The fourth andfinal load consisted of 7.78 kg's of SR mix #1 and 4.56 kg's ofpharmaceutical glaze. The entire pan was allowed to roll and cure underheat lamps for 6 hours before sampling for study.

Below is a list of all theoretical percentages and actual assay resultsfor the, above, described material.

Theoretical Actual Dissolution SR Mix PEH % PEH % 90 min, 3 hr, 6 hr #121.6% 20.8% 4.6%, 18.6%,  59.3% #2 19.8% 19.3% 0.2%, 0.8%, 11.0% #317.8% 17.3% 0.16%,  0.4%,  2.7% #4 15.5% 15.4% 0.6%, 0.8%,  2.6%

Based on assay and dissolution profile load #1 was selected for use infurther development. The moisture content in load #4 may be higher thanthose loads dried in the tray drier. This may have contributed to whyload #3 and #4 have essentially the same dissolution profile despite theincreased SR mix.

Dissolution: It was found that the dissolution rate of the phenylephrineis accelerated when combined with Gauifenesin DC. Due to this effect thetesting of the dissolution rate is achieved by first making a mock-up ofthe finished product. By doing so the suitability of the phenylephrinebeads was determined more accurately. Direct specifications fordissolution were determined once data was collected to accuratelypredict this rate change.

Example 2 Ionic Resin Mix

Another method of controlling the rate of availability involves usingcontrolled release matrices. One such controlled release bead includesadding one or more active agents to one or more resins or polymers. Tocontrol the rate of dissolution one or more of the following may beused: Dextromethorphan Polistirex Resin (15% ETC); PseudoephedrinePolistirex Resin (15% ETC); and/or Chlorpheniramine Polacrilex Resin(15% ETC). These resins may be used to deliver therapeutically effectiveamounts of Chlorpheniramine Polacrilex equivalent to ChlorpheniramineMaleate 6 mg/Dextromethorphan Polistirex equivalent to DextromethorphanHBr 30 mg/Pseudoephedrine Polistirex equivalent to Pseudoephedrine HC130mg per 5 ml dose.

TABLE 1 Basic Liquid Suspension Item Description Amount per 5 ml DoseQuantity required Purified Water, USP — 874 kg High Fructose Corn Syrup2800.00 mg 1120 kg Propylene Glycol, USP 387.50 mg 155 kg Split into 3parts - 50 kg/ 95 kg/10 kg Methylparaben 1.00 mg 0.40 kg Propylparaben0.25 mg 0.10 kg Polysorbate 80 25.00 mg 10.0 kg Xanthan Gum, NF 14.00 mg5.60 kg (Rhodigel 200) Red Opatint Dye 1.50 mg 0.60 kg (DG-15008)Strawberry Flavor 5.25 mg 2.10 kg (133.19035)

If only one lot of raw material Dextromethorphan Polistirex Resin (15%ETC) is required, the Assay Value is calculated and entered in thequantity required in kg (Dextromethorphan Polistirex Resin) column andin the Total quantity required in kg (Dextromethorphan Polistirex Resin)area.

If multiple lots of Dextromethorphan Polistirex Resin are required,multiply the calculated Assay Value of the partial lot(s) ofDextromethorphan Polistirex Resin by the kg available [quantity requiredin kg (Dextromethorphan Polistirex Resin)] to get the value. Thesevalues are recorded in the conversion factor column and enter the kgavailable of the partial(s) in the [quantity required in kg(Dextromethorphan Polistirex Resin)] column.

Divide the remaining conversion factor required by the calculated AssayValue of the lot of Dextromethorphan Polistirex Resin used to completethe weigh-up and enter the result in the corresponding quantity requiredin kg (Dextromethorphan Polistirex Resin) column. Total the quantityrequired in kg (Dextromethorphan Polistirex Resin) and enter this valuein the Total quantity required in kg (Dextromethorphan Polistirex Resin)area.

Divide each quantity required in kg (Dextromethorphan Polistirex Resin)by 0.4 (this 0.4 is a conversion factor for, e.g., a 2000 Liter batchsize) and enter the result(s) in the Amount per Dose in mg(Dextromethorphan Polistirex Resin) column. Total these values and enterthe result in the Total Amount per Dose in mg (DextromethorphanPolistirex Resin) area. The quantity required in kg is transferred(Dextromethorphan Polistirex Resin) and the amount per dose in mg(Dextromethorphan Polistirex Resin) results to the Formula & WeighupSheet.

If only one lot of raw material (Pseudoephedrine Polistirex Resin) isrequired, divide the conversion factor of 34.63 by the calculated AssayValue and enter the result in the quantity required in kg(Pseudoephedrine Polistirex Resin) column and in the Total quantityrequired in kg (Pseudoephedrine Polistirex Resin) area. Enter theconversion factor column or N/A are required.

If multiple lots of Pseudoephedrine Polistirex Resin are required,multiply the calculated Assay Value of the partial lot(s) ofPseudoephedrine Polistirex Resin by the kg available [quantity requiredin kg (Pseudoephedrine Polistirex Resin)] to get the Partial conversionfactor. Enter the value in the conversion factor column. Enter the kgavailable of the partial(s) in the [quantity required in kg(Pseudoephedrine Polistirex Resin)] column. Subtract the Partialconversion factor(s) from 34.63 to determine the remaining conversionfactor required. Enter this value in the appropriate space.

Divide the remaining conversion factor required by the calculated AssayValue of the lot of Pseudoephedrine Polistirex Resin used to completethe weigh-up and enter the result in the corresponding quantity requiredin kg (Pseudoephedrine Polistirex Resin) column. Total the quantityrequired in kg is determined and (Pseudoephedrine Polistirex Resin) thisvalue is entered in the total quantity required in kg (PseudoephedrinePolistirex Resin) area. Divide each quantity required in kg(Pseudoephedrine Polistirex Resin) by 0.4 (this 0.4 is a conversionfactor for, e.g., a 2000 Liter batch size) and enter the result(s) inthe Amount per Dose in mg (Pseudoephedrine Polistirex Resin) column.Total these values and enter the result in the Total Amount per Dose inmg (Pseudoephedrine Polistirex Resin) area. The quantity required in kgis transferred (Pseudoephedrine Polistirex Resin) and the amount perdose in mg (Pseudoephedrine Polistirex Resin) results to the Formula &Weighup Sheet.

If only one lot of raw material (Pseudoephedrine Polistirex Resin) isrequired, divide the conversion factor of 8.08 by the calculated AssayValue and enter the result in the quantity required in kg(Chlorpheniramine Polacrilex Resin) column and in the Total quantityrequired in kg (Chlorpheniramine Polacrilex Resin) area. Enter 8.08 inthe conversion factor column and N/A the unrequired rows.

If multiple lots of Chlorpheniramine Polacrilex Resin are required,multiply the calculated Assay Value of the partial lot(s) ofChlorpheniramine Polacrilex Resin by the kg available [quantity requiredin kg (Chlorpheniramine Polacrilex Resin)] to get the Partial conversionfactor. Enter this(these) value(s) in the conversion factor column.Enter the kg available of the partial(s) in the [quantity required in kg(Chlorpheniramine Polacrilex Resin)] column.

Subtract the Partial conversion factor(s) from 8.08 to determine theremaining conversion factor required. Divide the remaining conversionfactor required by the calculated Assay Value of the lot ofChlorpheniramine Polacrilex Resin used to complete the weigh-up andenter the result in the corresponding quantity required in kg(Chlorpheniramine Polacrilex Resin) column.

Total the quantity required in kg (Chlorpheniramine Polacrilex Resin)and enter this value in the Total quantity required in kg(Chlorpheniramine Polacrilex Resin) area. Divide each quantity requiredin kg (Chlorpheniramine Polacrilex Resin) by 0.4 (this 0.4 is aconversion factor for a 2000 Liter batch size) and enter the result(s)in the Amount per Dose in mg (Chlorpheniramine Polacrilex Resin) column.Total these values and enter the result in the Total Amount per Dose inmg (Chlorpheniramine Polacrilex Resin) area. Transfer the quantityrequired in kg (Chlorpheniramine Polacrilex Resin) and the Amount perDose in mg (Chlorpheniramine Polacrilex Resin) results to the Formula &Weighup Sheet.

Resin Blending Instructions. Again, all personnel involved in themanufacturing process must wear appropriate attire and use theappropriate safety equipment. Rooms and binder, e.g., a 20 ft3V-Blender, are first checked for cleanliness and the observations arerecord in the Cleaning, Maintenance & Use Log(s). All equipment,utensils, and containers are also checked for cleanliness and the room,equipment, and containers labeled as required.

Transfer Methocel to the Blender. Blend for 2 minutes. Next, addDextromethorphan Polistirex Resin to the Blender, PseudoephedrinePolistirex Resin and Chlorpheniramine Polacrilex Resin to the Blender.Blend for 5 minutes. Discharge the Blender into 2 separate medium sized,pre-weighted, plastic-lined containers (≈36 kg each) labeled “ResinBlend”. Make sure that all of the material is removed from the blenderand put aside for preparation of the liquid formulation.

TABLE 2 Basic 3 Active Blend Item Description Amount per 5 ml DoseDextromethorphan 30 mg Polistirex Resin (15% ETC) Pseudoephedrine 30 mgPolistirex Resin (15% ETC) Chlorpheniramine  6 mg Polacrilex Resin (15%ETC) Methocel E5LV 19.25 mg   (hydroxypropyl methylcellulose, USP)Purified Water, USP qs

TABLE 3 Basic Two Active Blend Item Description Amount per 5 ml DosePseudoephedrine   30 mg Polistirex Resin (15% ETC) Chlorpheniramine    6mg Polacrilex Resin (15% ETC) Methocel E5LV 19.25 mg (hydroxypropylmethylcellulose, USP) Purified Water, USP qs

Suspension Blending Instructions. All personnel involved in themanufacturing process must wear appropriate attire and use theappropriate safety equipment. When using the Diaphragm Pump(s) allow thesolution supply valve to be opened and the liquid from the feed solutionis allowed to prime the pump prior to starting the pump. This is done toprevent the introduction of air into the feed solution. When using theDiaphragm Pump(s) to transfer any solution containing Propylene Glycolmake sure that the lines are completely drained to avoid theintroduction of water into the solution.

Check room and the oven (or heating device) and check the ProcessingSweep Tank for cleanliness. All steps in the process should generally byrecorded in the Cleaning, Maintenance & Use Log(s). Check room andappropriately sized Open Top Processing Tank for cleanliness. Set up aDiaphragm Pump(s) and check for cleanliness. Record in the Cleaning,Maintenance & Use Log(s). Set up an 87 gallon Plastic Processing Tank,e.g., an 87 gallon processing tank, with a mixer and check forcleanliness. Set up an appropriately sized Electric Kettle and check forcleanliness. Verify the cleanliness of the disassembled valves, hoses &connections, and other miscellaneous equipment/hardware. Check allutensils and containers for cleanliness. Label the room, equipment, andcontainers as required.

As shown in FIG. 2, the thickening branch of the method is depicted.First, the valves and connections of all the vessels or containers arechecked to ensure that they are clean and that all valves are in theclosed position. In block 200, the syrup is heated, e.g., corn syrup isplaced in the heater/oven or alternate heating device at ≈45° C. for 8to 12 hours (generally greater than 6 hours, block 202). Next, in block204, the thickening agent is transferred, e.g., corn syrup to theProcessing Sweep Tank using a diaphragm pump or like pump that minimizesor generally eliminates the introduction of air or air bubbles into thesyrup. If adding the thickening agent from the top of a vessel, the flowof the syrup from the pump to the tank should be directed to the side ofthe tank at a volume and with flow slow enough that the syrup slidesdown the side of the tank introduces as little air as possible into thesyrup, e.g., in a large batch 800 liters (block 206) and the thickenerand water are mixed with a low or reduced cavitation propeller mixer,paddle mixer and the like. Alternatively, the vessel itself may beheated thereby eliminating the need for transfer of the liquid; however,in such circumstances the thickening agent should still be introducedinto the vessel so as to minimize bubble formation. In block 208, thethickener or syrup is allow to rest for about 30 minutes or more toallow the syrup to settle and if necessary to allow for cooling and orreduction of the temperature to, e.g., room temperature. In block 210,the thickener is prepared for transfer into a larger vessel for finalmixing using, e.g., a diaphragm or other like pump.

For transfer of the thickener or syrup, the lines for transfer will beflushed and/or primed through the diaphragm pump with, e.g., 20 kg ofpurified water to the processing sweep tank. For final transfer to alarger final tank, the flow from the pump to the tank should be directedto the side of the tank slow enough that the corn syrup/purified waterslides down the side of the tank, introducing as little air as possible.Allow the corn syrup to sit undisturbed (usually about 30 minutes) toallow any air bubbles to subside.

FIG. 3 summarizes the preparation of a polyethylene glycol preservativemix. Transfer approximately 800 kg of purified water to the open topprocessing tank using the diaphragm pump (if needed) transfer the 50 kgportion of propylene glycol to the electric kettle and heat thispropylene glycol up to but not to exceed 60° C.)(block 300). Next, inblock 302 a preservative, e.g., methylparaben and/or propylparaben tothe electric kettle. Label the kettle “paraben solution”. The parabensmay be transferred to the kettle at any point during the heatingprocess. Intermittently mix the paraben solution in the electric kettleuntil dissolved. Also in block 302, a surfactant and/or emulsifyingagent, e.g., polysorbate 80, is added to the kettle containing the“paraben solution” and mix until the two phases combine to form oneclear phase. If the temperature of the solution has cooled significantlyit may need to reheated (not to exceed 60° C.) to form one clear phase.Label the kettle “paraben/polysorbate 80 solution.” Transfer the 95 kgportion of propylene glycol to a plastic processing tank. Transfer the“paraben/polysorbate 80 solution” to the 87 gallon plastic processingtank. Rinse the electric kettle to the 87 gallon plastic processing tankwith the 10 kg portion of propylene glycol.

FIG. 4 is flow chart of the method for preparing a thixotropic agent. Inblock 400, a thixotropic agent such as xanthan gum, is added to, e.g.,the “paraben/polysorbate 80 solution” in a processing tank and mix toslurry (usually about 10 minutes)(block 402). The xanthan gum willgenerally not dissolve in this slurry, therefore, it is preferable thatthe slurry not be allowed to stand without mixing because the xanthangum will settle (block 404). Finally, in block 406, processing tank'smixer is turned on and the mixture is clarified and/or made generallyhomogenous, taking care to minimize bubble formation for about 1 hour ormore. The mixer may remain “on” for the remainder of the manufacturingprocess.

As shown in FIG. 5, the preservative mix, e.g., the paraben/polysorbate80/xanthan gum mixture, is transferred to the open top processing tank(block 500). Again, the flow of the solution to the tank should bedirected to the side of the tank so that as little air as possible isintroduced. Mix the solution in the open top processing tank for aminimum of 1 hour, without introducing any air, until the solution ishomogeneous (uniform appearance with no visible lumps). Next, in block502, a colorant is added, e.g., red opatint dye, and flavorant, e.g.,strawberry flavor to the open top processing tank. Rinse each containerto the open top processing tank with approximately 2 kg of purifiedwater. At block 506, gradually sprinkle the “resin blend” to the opentop processing tank. Continue mixing for a minimum of 30 minutes,without introducing any air, until the solution is homogeneous (uniformappearance with no visible lumps). Alternatively, using the diaphragmpump carefully transfer the solution in the open top processing tank tothe processing sweep tank containing the thickening agent (block 504),e.g., the corn syrup. The flow of the solution from the open topprocessing tank to the processing sweep tank should be directed belowthe surface of the corn syrup introducing as little air as possible(block 508). Rinse the open top processing tank to the processing sweeptank with approximately 50 kg of purified water. Install the electricmixer in the processing sweep tank and submerge the propeller to theinterface of the corn syrup and the solution from the open topprocessing tank. Angle the mixer propeller so that it does not interferewith the tank sweepers and it does not introduce air to the solutionduring operation or scrape the sides of the vessel or tank.

Turn the sweepers of the processing sweep tank on at the minimum speedto check for clearance in relation to the propeller of the electricinterface mixer (block 510), without adding the scrapers or spatulasthat are often used with general liquid mixing. Increase the speed ofthe tank sweepers to, e.g., 45 Hertz and turn on the tank mixer to,e.g., 31 Hertz. While still running the tank sweepers and the tankmixer, turn on the electric interface mixer and mix for 15 minutes. Ifany air is being introduced into the solution turn off the electricinterface mixer immediately and repeat the propangle adjustment/sweeperinterference procedure.

Using the diaphragm pump at a maximum of, e.g., 30 psi recirculate thesolution in the processing sweep tank for 15 minutes. The flow of thesolution from the pump to the tank should be directed approximately onefoot below the surface of the suspension introducing as little air aspossible. Turn off and remove the electric interface mixer and increasethe speed of the tank sweepers to, e.g., 90 Hertz while maintaining thetank mixer at 31 Hertz. Unless otherwise specified, the tank sweepersand mixer should remain on throughout the remainder of the manufacturingand packaging process.

Turn off the sweepers (leave the mixer on) to the processing sweep tankand remove the recirculation pipe prior to this qs step. Using thediaphragm pump qs to, e.g., 2400 kg with purified water. The flow ofpurified water from the pump to the tank should be directed to the sideof the tank slow enough that it slides down the side of the tankintroducing as little air as possible. Immediately after the qs step hasbeen completed, turn the tank sweepers back on at, e.g., 90 Hertz.

Reinstall the recirculation pipe approximately one foot below thesurface of the suspension. Continue to sweep and mix, along withrecirculation using the diaphragm pump at a maximum of, e.g., 30 psi,the solution in the processing sweep tank for, e.g., 45 minutes.Generally and depending on the materials, the following steps should beperformed quickly so that the solution does not sit without mixing.Assure that all mixing is off (recirculation should remain on) andremove a small sample in a clear container.

Notify quality assurance that the batch is ready for sampling if thetests performed in prior steps are acceptable. Sample the batch belowthe surface using the sampling tool. Make sure that the appropriatesamples are removed. Turn the sweeper (at 45 Hertz) and mixer (at 31Hertz) back on. Reset the recirculation pipe (at 30 psi) so that it is 1foot from the agitation plate of the sweeper. Unless otherwise specifiedherein, these settings may remain constant. Make sure that a 10 meshin-line filter is installed after the pump used to transfer thesuspension to the packaging line.

FIG. 6-8 are graphs that demonstrate the release profile of two activeagents in a liquid formulation of the present invention. The dissolutionprofiles of active agents in a sustained-release liquid formulation ofthe present invention was tested using, e.g., a standard low pH or awater dissolution profile assays. Briefly, the sustained release activeswere tested for percent release by dissolution in a 37 degree Celsiuswater bath in one liter of deionized water into which 5.0 grams ofpotassium chloride was dissolved with paddles that mix the sample at 150revolutions per minute (RPMs). A 5 milliliter test sample of the liquidformulation, neat or titrated, is added to the bath using a syringe(which may be washed in the water/KCl mix). Aliquots of 2 ml are sampledat, e.g., 0.5, 1, 3 and 8 hours. The results of a two active agentformulation and release are shown for three different samples in FIGS.6-8. The exact formulation used was taught hereinabove in example 2.

FIG. 9-11 are graphs that demonstrate the release profile of thirdactive agents in a liquid formulation of the present invention. Thesegraphs demonstrate the release profile of three active agents in aliquid formulation of the present invention. The dissolution profiles ofactive agents in a sustained-release liquid formulation of the presentinvention was tested using, e.g., a standard low pH or a waterdissolution profile assays. Briefly, the sustained release actives weretested for percent release by dissolution in a 37 degree Celsius waterbath in one liter of deionized water into which 5.0 grams of potassiumchloride was dissolved with paddles that mix the sample at 150revolutions per minute (RPMs). A 5 milliliter test sample of the liquidformulation, neat or titrated, is added to the bath using a syringe(which may be washed in the water/KCl mix). Aliquots of 2 ml are sampledat, e.g., 0.5, 1, 3 and 8 hours. The results of a three active agentformulation and release are shown for three different samples in FIGS.6-8.

It will be understood that particular embodiments described herein areshown by way of illustration and not as limitations of the invention.The principal features of this invention can be employed in variousembodiments without departing from the scope of the invention. Thoseskilled in the art will recognize, or be able to ascertain using no morethan routine experimentation, numerous equivalents to the specificprocedures described herein. Such equivalents are considered to bewithin the scope of this invention and are covered by the claims.

All publications and patent applications mentioned in the specificationare indicative of the level of skill of those skilled in the art towhich this invention pertains. All publications and patent applicationsare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated by reference.

All of the compositions and/or methods disclosed and claimed herein canbe made and executed without undue experimentation in light of thepresent disclosure. While the compositions and methods of this inventionhave been described in terms of preferred embodiments, it will beapparent to those of skill in the art that variations may be applied tothe compositions and/or methods and in the steps or in the sequence ofsteps of the method described herein without departing from the concept,spirit and scope of the invention. More specifically, it will beapparent that certain agents which are both chemically andphysiologically related may be substituted for the agents describedherein while the same or similar results would be achieved. All suchsimilar substitutes and modifications apparent to those skilled in theart are deemed to be within the spirit, scope and concept of theinvention as defined by the appended claims.

1-34. (canceled)
 35. A liquid, controlled-release formulation comprisingcontrolled release microbeads comprising one or more active agents incoated drug-resin complexes, a dense, thixotropic solution having adensity that is at or about the density of the one or more microbeads,said dense, thixotropic solution comprising a thixotropic agent, waterand one or more preservatives, wherein said formulation is shelf-stableand has a uniform appearance with no visible lumps, and further whereinsaid formulation is made by the method of obtaining one or morecontrolled release microbeads comprising one or more active agents incoated drug-resin complexes; preparing a dense, thixotropic solutionhaving a density that is at or about the density of the one or moremicrobeads, wherein the dense, thixotropic solution comprises athixotropic agent, water and one or more preservatives, under conditionsthat reduce bubble formation; and mixing the microbeads and thethixotropic solutions under conditions that minimize the introduction ofbubbles in the liquid.
 36. The liquid formulation of claim 35, whereinthe one or more active agents comprises pseudoephedrine, salts thereofor mixtures of salts thereof.
 37. The liquid formulation of claim 35,wherein the one or more active agents comprises an antihistamine. 38.The liquid formulation of claim 35, wherein the one or more activeagents comprises chlorpheniramine, salts thereof or mixtures of saltsthereof.
 39. The liquid formulation of claim 35, wherein the one or moreactive agents comprises dextromethorphan, salts thereof or mixtures ofsalts thereof.
 40. (canceled)
 41. The liquid formulation of claim 35,wherein the one or more active agents comprises an analgesic.
 42. Theliquid formulation of claim 35, wherein the one or more active agentscomprises an antitussive.
 43. (canceled)
 44. A liquid,controlled-release formulation comprising controlled release beadscomprising one or more active agents in coated drug-resin complexes witha dense, thixotropic solution having a density that is at or about thedensity of the one or more beads, wherein the dense, thixotropicsolution comprises a thixotropic agent, water and one or morepreservatives, wherein said formulation is shelf-stable and has auniform appearance with no visible lumps, and further wherein saidformulation is made by the method of blending one or more controlledrelease beads comprising one or more active agents in coated drug-resincomplexes with a dense, thixotropic solution with a density that is ator about the density of the one or more beads, wherein the dense,thixotropic solution comprises a thixotropic agent, water and one ormore preservatives, under conditions that minimize air bubbles whichcling to said beads.
 45. The liquid formulation of claim 44, whereinsaid method comprises the step of blending a mixture comprising one ormore controlled-release beads comprising one or more active agents, athickening agent and a surfactant by mixing with a low cavitationpropeller and recirculating the mixture under the surface of the mixtureso as to minimize bubble formation. 46-60. (canceled)
 61. The liquidformulation of claim 35, wherein the one or more microbeads comprise oneor more of the following: an enteric coat, a resin coat, a lacquer coat,a pH-sensitive coating, a biodegradable polymer matrix, a water solublematrix, an ionic matrix, combinations and mixtures thereof.
 62. Theliquid formulation of claim 35, wherein the one or more microbeadscomprise one or more polymers selected from the group consisting ofcellulose, ethylcellulose, methylcellulose, propylcellulose,methoxypropylcellulose, cellulose nitrate, poly(vinyl alcohol),poly(vinyl chloride), polystyrene, polyethylene, polypropylene,poly(ethylene-co-vinyl acetate), poly(hydroxybutyric acid),poly(hydroxyvalerianic acid-co-hydroxybutyric acid), poly(lactic acid),poly(glycolic acid), poly(lactic acid-co-glycolic acid),poly(ε-caprolactones), poly(ε-caprolactone-co-DL-lactic acid),poly(maleic anhydride), polyamides, gelatin, chitosan, collagen,poly(hydroxyalkyl)-L-glutamines, poly(γ-ethyl-L-glutaminate-co-glutamicacid), poly(L-leucine-co-L-aspartic acid), poly(proline-co-glutamicacid), poly(alkyl 2-cyanoacrylates), polyurethanes, poly(methylmethacrylate), poly(methyl methacrylate-co-methacrylic acid) andpoly(methacrylate-co-hydroxypropyl methacrylate), polystirex, salts,combinations and mixtures thereof.
 63. The liquid formulation of claim35, wherein the conditions that reduce bubble formation comprise thestep of using a diaphragm pump to combine the water and the thixotropicagent and one or more preservatives, colorants and flavorants.
 64. Theliquid formulation of claim 35, wherein the conditions that reducebubble formation and/or minimize the introduction of bubbles comprisethe step of placing the recirculating tube below the surface of theliquid.
 65. The liquid formulation of claim 35, wherein the conditionsthat reduce bubble formation and/or minimize the introduction of bubblescomprise the step of adding liquids along the side of a vessel holdingthe liquid.
 66. The liquid formulation of claim 35, wherein theconditions that minimize the introduction of bubbles comprise the stepof sprinkling the beads onto the surface of the liquid.
 67. The liquidformulation of claim 35, wherein the conditions that minimize theintroduction of bubbles comprise the step of mixing the solution in theabsence of one or more paddles that scrape the vessel.
 68. The liquidformulation of claim 35, wherein the conditions that reduce bubbleformation comprise the step of using a diaphragm pump to combine one ormore of the water, the thixotropic agent, the one or more preservatives,colorants and flavorants.
 69. The liquid formulation of claim 35,wherein the conditions that reduce bubble formation and/or minimize theintroduction of bubbles comprise the steps of: placing a recirculatingtube below the surface of the liquid; adding liquids along the side of avessel holding the liquid; and using a mixer that lacks scrapingpaddles.
 70. The liquid formulation of claim 35, wherein the conditionsthat reduce bubble formation and/or minimize the introduction of bubblescomprise the step of mixing the solution with a propeller mixer.
 71. Theliquid formulation of claim 35, wherein the conditions that reducebubble formation and/or minimize the introduction of bubbles comprisethe step of mixing the solution with a propeller mixer at a speed thatreduces cavitation.
 72. The liquid formulation of claim 35, wherein theconditions that reduce bubble formation and/or minimize the introductionof bubbles comprise the step of mixing the solution with a propellerthat minimizes cavitation.
 73. The liquid formulation of claim 35,wherein a portion of the one or more beads comprises an immediaterelease profile and another portion comprise a delayed release profile.74. The liquid formulation of claim 35, wherein the formulation furthercomprises one or more flavorants, one or more surfactants, one or moredissolved active agents, one or more buffers, one or more excipients, ormixtures and combinations thereof.
 75. The liquid formulation of claim35, wherein the one or more active agents are pharmaceutical agents. 76.The liquid formulation of claim 35, wherein the one or more activeagents comprise vitamins, minerals, nutritional supplements, herbalextracts, gums, gels, oils, salts, or mixtures and combinations thereof.77. The liquid formulation of claim 35, wherein the one or more activeagents are pharmaceutical agents selected from the group consisting ofprotein, peptide, carbohydrate, polysaccharide, glycoprotein, lipid,hormone, growth factor, cytokine, interferon, receptor, antigen,allergen, antibody, antiviral, antifungal, antihelminthic, substrate,metabolite, cofactor, inhibitor, drug, pharmaceutical, nutrient, toxin,poison, explosive, pesticide, chemical warfare agent, biowarfare agent,biohazardous agent, infectious agent, prion, radioisotope, vitamin,heterocyclic aromatic compound, carcinogen, mutagen, narcotic,amphetamine, barbiturate, hallucinogen, combinations and mixturesthereof.
 78. The liquid formulation of claim 35, wherein the one or moreactive agents comprise a pharmaceutical agent, an enzyme, a cytokine, agrowth promoting agent, an antibody, an antigen, a hormone, a vaccine, acell, a live-attenuated pathogen, a heat-killed pathogen, a virus, abacteria, a fungi, a peptide, a carbohydrate, a nucleic acid, a lipid,or mixtures and combinations thereof.
 79. The liquid formulation ofclaim 35, wherein the one or more active agents may be steroids,respiratory agents, sympathomimetics, local anesthetics, antimicrobialagents, antiviral agents, antifungal agents, antihelminthic agents,insecticides, antihypertensive agents, antihypertensive diuretics,cardiotonics, coronary vasodilators, vasoconstrictors, β-blockers,antiarrhythmic agents, calcium antagonists, anti-convulsants, agents fordizziness, tranquilizers, antipsychotics, muscle relaxants, drugs forParkinson's disease, respiratory agents, hormones, non-steroidalhormones, antihormones, vitamins, antitumor agents, miotics, herbmedicines, antimuscarinic, interfereons, immunokines, cytokines,muscarinic cholinergic blocking agents, mydriatics, psychic energizers,humoral agents, antispasmodics, antidepressant drugs, anti-diabetics,anorectic drugs, anti-allergenics, decongestants, expectorants,antipyretics, antimigrane, anti-malarials, anti-ulcerative, peptides,anti-estrogen, anti-hormone agents, antiulcer agents, anesthetic agent,drugs having an action on the central nervous system, protein, peptide,carbohydrate, polysaccharide, glycoprotein, lipid, hormone, growthfactor, cytokine, interferon, receptor, antigen, allergen, antibody,substrate, metabolite, cofactor, inhibitor, drug, pharmaceutical,nutrient, toxin, poison, explosive, pesticide, chemical warfare agent,biowarfare agent, biohazardous agent, infectious agent, prion,radioisotope, vitamin, heterocyclic aromatic compound, carcinogen,mutagen, narcotic, amphetamine, barbiturate, hallucinogen, and vaccinesagainst virus, bacterium, fungi, helminth, cancer, Salmonella,Streptococcus, Brucella, Legionella, E. coli, Giardia, Cryptosporidium,Rickettsia, spore, mold, yeast, algae, amoebae, dinoflagellate,unicellular organism, pathogen, or combinations and mixtures thereof.80. The liquid formulation of claim 35, wherein the one or more activeagents comprises an analgesic.
 81. The liquid formulation of claim 35,wherein the one or more active agents comprises an antitussive.
 82. Theliquid formulation of claim 35, wherein the one or more active agentscomprises a narcotic.
 83. The liquid formulation of claim 35, whereinthe one or more active agents are disposed on a poly-lactic acid (PLA),poly-glycolic acid (PGA) and/or poly-lactic polyglycolic acid (PGLA)bead.
 84. A liquid, controlled-release formulation comprising controlledrelease microbeads comprising one or more active agents in coateddrug-resin complexes, a dense, thixotropic solution having a densitythat is at or about the density of the one or more microbeads, saiddense, thixotropic solution comprises a thixotropic agent, water and oneor more preservatives, wherein said formulation is shelf-stable and hasa uniform appearance with no visible lumps.
 85. The liquid,controlled-release of claim 84, wherein the microbeads are free ofbubbles that cling to said microbeads and change their nominal density.